Molecular mechanisms controlling skin heterogeneity

控制皮肤异质性的分子机制

• 批准号: 10669251
• 负责人: Sarah E. Millar
• 金额: $ 56.37万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669251
• 关键词: ATAC-seq; Acne; Address; Adipocytes; Adult; Affect; Area; Candidate Disease Gene; Cells; Characteristics; Chromatin; Chromatin Structure; DNA Methylation; DNA Modification Process; Data; Dermal; Dermis; Development; Disease; Dorsal; Ear; Embryo; Embryonic Development; Enhancers; Epidermis; Epigenetic Process; Experimental Genetics; Extensor; Fetal Development; Fibroblasts; Gene Deletion; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic study; Growth; Hair; Hair follicle structure; Heterogeneity; Hi-C; Histology; Human; Leg; Life; Location; Maintenance; Male Pattern Baldness; Molecular; Multiomic Data; Mus; Natural regeneration; Nature; Palmoplantar Keratosis; Pathway interactions; Pattern; Phenotype; Pigmentation physiologic function; Population; Psoriasis; Quality of life; Rare Diseases; Repression; Sampling; Scalp structure; Signal Transduction; Site; Skin; Skin graft; Sweat Glands; System; Testing; Therapeutic; Thick; Tissue-Specific Gene Expression; Variant; Vitiligo; XCL1 gene; bisulfite sequencing; candidate identification; cell type; comparative; density; differential expression; experimental study; face skin; fetal; genetic analysis; hair regeneration; histone modification; improved; in vivo; inhibitor; loss of function; mouse genetics; mouse model; multiple omics; nerve supply; new therapeutic target; novel; postnatal; programs; regional difference; response to injury; single cell analysis; single-cell RNA sequencing; skin disorder; skin organogenesis; therapeutic target; tongue papilla; tool; transcription factor; transcriptome sequencing; wound healing

Different regions of the skin vary in their characteristics such as thickness, pigmentation, innervation, and presence, size and density of hair follicles and sweat glands, that are reflected in differential responses to injury and disease. As examples, androgenetic alopecia is limited to the scalp; acne predominates in facial skin; psoriasis is often most prominent in extensor regions; palmoplantar keratoderma is limited to palms and soles; and vitiligo can appear in symmetrical patterns. While regional characteristics of the skin are established during fetal development, positional information must be retained in the skin throughout life to allow for maintenance of regional characteristics and their re-establishment in wound healing. Positional information is known to reside in the skin dermis, but its molecular basis is poorly understood. To address this question, we propose the following Specific Aims. AIM 1: To identify candidate factors and areas of chromatin involved in establishing skin heterogeneity in embryogenesis we will analyze transcriptional profiles through single cell RNA-seq, and chromatin structure via single cell ATAC-seq, in distinct regions of developing skin to identify those that show region-specific expression or openness, respectively. AIM 2: (i) To determine which of these candidate factors and chromatin areas may also be responsible for maintaining regional skin heterogeneity in adult life, we will perform the same analyses on the corresponding areas of adult skin. (ii) We hypothesize that epigenetic mechanisms contribute to maintenance of regional skin characteristics. To test this, we will first identify patterns of DNA methylation and histone modifications that characterize developing dermis in specific skin regions by carrying out Bisulfite-seq to reveal sites of DNA methylation, and CUT&RUN for histone modifications that mark enhancers and active, repressed, or poised genes. We will then ask which of these patterns are maintained in adult dermal cells from the same regions. AIM 3: To test the functions of candidate regulators in directing and maintaining region-specific differentiation programs, we will use inducible genetic tools to delete the corresponding genes in developing or adult mouse dermis in vivo. Together, these experiments provide a comprehensive and unbiased approach to identify novel mechanisms that establish and maintain skin heterogeneity. Improved understanding of these mechanisms has potential to reveal new therapeutic targets in wound healing and in common and rare diseases that affect specific skin regions and have a major negative impact on quality of life; data obtained in this project will also inform strategies for generating specific skin types, including hair follicle- and sweat gland-bearing skin, for reparative skin grafting.

皮肤的不同区域的特征不同，例如厚度，色素沉着，神经和 毛囊和汗腺的存在，大小和密度，反映在对 伤害和疾病。作为例子，雄激素脱发仅限于头皮。痤疮在面部占主导地位 皮肤;牛皮癣通常在伸肌地区最突出。 Palmoplantar keratoderma仅限于手掌， 鞋底；白癜风可以以对称模式出现。虽然建立了皮肤的区域特征 在胎儿发育期间，必须将位置信息保留在皮肤中，以允许 维持区域特征及其在伤口愈合中的重建。位置信息是 已知居住在皮肤真皮中，但其分子基础知之甚少。为了解决这个问题，我们 提出以下特定目标。目的1：确定候选因素和染色质的区域 在胚胎发生中建立皮肤异质性，我们将通过单细胞分析转录曲线 RNA-seq和通过单细胞ATAC-SEQ的染色质结构，在发育中的不同区域，以鉴定 那些分别显示特定区域表达或开放性的人。目标2：（i）确定其中哪一个 候选因素和染色质区域也可能负责维持区域皮肤异质性 成人生活，我们将对成人皮肤的相应区域进行相同的分析。 （ii）我们假设 表观遗传机制有助于维持区域皮肤特征。为了测试这一点，我们将首先 识别DNA甲基化和组蛋白修饰的模式，这些模式表征了特定的真皮 皮肤区域通过执行Bisulfite-seq来揭示DNA甲基化位点，并切割和运行组蛋白 标记增强子并活跃，抑制或固执的基因的修改。然后，我们将询问其中哪一个 模式在来自相同区域的成年皮细胞中保持。目标3：测试候选人的功能 指导和维护特定区域分化计划的监管机构，我们将使用诱导的遗传 在体内发育或成年小鼠真皮中删除相应基因的工具。在一起，这些 实验提供了一种全面且公正的方法，可以识别建立和 保持皮肤异质性。对这些机制的理解的提高有可能揭示新的 伤口愈合以及影响特定皮肤区域的常见和罕见疾病中的治疗靶标 对生活质量产生重大负面影响；该项目中获得的数据还将为 产生特定的皮肤类型，包括毛囊和汗腺的皮肤，用于修复皮肤。